DE102009041839A1 - Preparation of a donepezil-containing tablet, useful for treating mild to moderate dementia of the Alzheimer type, comprises wet granulation of donepezil with granulating liquid and excipients e.g. cellulose and starch - Google Patents

Abstract

Preparation of a donepezil-containing tablet (I) comprises wet granulation of donepezil with granulating liquid and excipients. An independent claim is included for the tablet obtained by the above method. ACTIVITY : Nootropic. MECHANISM OF ACTION : None given.

Description

The present invention relates to a process for the preparation of donepezilhaltigen tablets, such as. Uncoated tablets, coated tablets (film-coated tablets), orodispersible tablets.

Donepezil is a piperidine derivative approved as an anti-dementive in the form of hydrochloride. It is suitable for the symptomatic treatment of mild to moderate dementia of the Alzheimer type.

Pharmaceutically used is a racemate of (R) and (S) form, which is marketed under the brand Aricept ^® . Donepezil hydrochloride is a white, crystalline powder with good solubility in chloroform, moderate solubility in water and acetic acid, low solubility in ethanol and acetonitrile, and practical insolubility in ethyl acetate and hexane.

• – schnelle Wirkstofffreisetzung;
• – schneller Zerfall der Tabletten bzw. Filmtabletten, um eine schnelle Auflösung des Wirkstoffes zu befördern
• – eine rasche Auflösung in wässrigem Medium, insbesondere in 0,1 N HCl Lösung und physiologisch relevanten Pufferlösungen mit pH-Werten von 4,6 und 6,8;
• – wirtschaftlicher Herstellungsprozess mit möglichst wenig Schritten und einer Proportionalität bei der Herstellung;
• – hinreichende Stabilität, um eine Haltbarkeit von mindestens drei Jahren zu gewährleisten.

For a tablet, a number of properties are desirable. These include:

• - rapid release of active ingredient;
• - Rapid disintegration of the tablets or film-coated tablets in order to promote a rapid dissolution of the active ingredient
• A rapid dissolution in an aqueous medium, in particular in 0.1 N HCl solution and physiologically relevant buffer solutions with pH values of 4.6 and 6.8;
• - economic manufacturing process with as few steps and a proportionality in the production;
• - sufficient stability to ensure a shelf life of at least three years.

Due to the high degree of fineness of the powdered active ingredient (90% <30 microns) and its high solubility is to be expected that the direct compression of an active ingredient / excipient mixture is the manufacturing method of choice for producing fast-release tablets with good dosing accuracy. The application of a water-soluble film coating is optional. He serves z. B. the taste coverage or color and is to be interpreted so that the drug release is not affected.

Corresponding studies on the direct processing of Donepezil-containing powder mixtures showed, however, that the recovery of the amount of active ingredient used is not guaranteed in the case of direct compression. In fact, drug losses of more than 5% by weight occurred. It was found that the active ingredient unfolded a considerable affinity for the container surfaces in the dry mixing, which led to an active ingredient depletion in the powder compact. Even with inert glass mixing vessels, this drug depletion could be verified to an extent of greater than 5% by weight.

The object of the present invention was to provide a simple process for the preparation of donepezilhaltigen tablets, which meets at least some of the above properties and also achieves a high drug recovery rate or minimizes drug losses.

The object is achieved by a process for producing a tablet containing donepezil comprising the step of wet granulation of donepezil with a granulating liquid together with excipients.

According to the invention, donepezil is firstly dissolved or suspended in a solvent and then mixed with the customary excipients to form a moist granulate. Subsequently, the moist granules are dried and pressed after mixing with other excipients to tablets. On top of this, a film coating is then optionally sprayed on in a further production step.

Suitable auxiliaries are in particular tablet fillers, tablet fillers and tablet binders or mixtures of these substances in question. Examples of these are cellulose, microcrystalline cellulose, starch, lactose, sorbitol, mannitol, xylitol, isomalt, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, silicon dioxide.

As a granulating liquid in which donepezil or the donepezil derivative is first dissolved or suspended, in particular water, ethanol, isopropanol, n-propanol, polyethylene glycol, glycerol, acetone and mixtures thereof have proven useful.

Preferably, the donepezil is first dissolved, not only suspended.

In a preferred embodiment, the total weight of the tablet obtained is 10 to 60 times the weight of the active ingredient, preferably 10 to 30 times.

A preferred derivative of donepezil is donepezil hydrochloride.

In one embodiment of the invention, the tablet is subsequently provided with a film coating.

The invention also relates to a tablet containing donepezil, which is obtainable by the method according to the invention.

It may be z. This may be, for example, an uncoated tablet, a coated tablet (film-coated tablet) or an orodispersible tablet.

1 and 2 show results of the investigation of the dissolution behavior according to Example 17.

3 and 4 show results of the investigation of the dissolution behavior according to Example 18.

The invention is explained in more detail by the following examples.

Example 1: (Comparative Example)

The following ingredients were compressed by direct compression into tablets of dose 5 mg: donepezil hydrochloride 5 mg lactose 75 mg Microcrystalline cellulose 33 mg Hydroxypropylcellulose, low subst. 6 mg magnesium stearate 1 mg

Similarly, in the second trial, tablets of dose strength 10 mg were prepared by direct compression: donepezil hydrochloride 10 mg lactose 150 mg Microcrystalline cellulose 66 mg Hydroxypropylcellulose, low subst. 12 mg magnesium stearate 2 mg

The 5 mg tablets were pressed to a diameter of 7 mm, the 10 mg tablets to a diameter of 9 mm. Finally, the tablets were coated with a Polyvinylalkokol-containing paint dispersion. The tablets exhibited good mechanical stability with rapid disintegration and rapid in vitro drug release in 0.1 N hydrochloric acid.

Example 2: (Comparative Example)

In a further experiment, the following ingredients were compressed by direct compression: donepezil hydrochloride 5 mg mannitol 68.35 mg Microcrystalline cellulose 30.25 mg Hydroxypropylcellulose, low subst. 5.5 mg magnesium stearate 0.9 mg

Tablets were also prepared with the double dosage: donepezil hydrochloride 10 mg mannitol 136.7 mg Microcrystalline cellulose 60.5 mg Hydroxypropylcellulose, low subst. 11 mg magnesium stearate 1.8 mg

The 5 mg tablets were pressed to a diameter of 7 mm, the 10 mg tablets to a diameter of 9 mm. Finally, the tablets were coated with a hydroxypropylmethyl cellulose-containing paint dispersion. The tablets exhibited good mechanical stability with rapid disintegration and rapid in vitro drug release both in 0.1 N hydrochloric acid and in aqueous buffer solution pH 6.8.

Example 3:

Subsequently, the recovery rate of 10 tablets was determined analytically. It was 94.15 +/- 0.65% for the lactose-containing tablets (Example 1) and 94.28 +/- 1.17% for various studies of manitol-containing products (Example 2), 94.60 +/- 1.49% and 93.72 +/- 0.85%. As a cause of the apparent loss of active ingredient of the tablets could be determined in further investigations an active ingredient depletion in dry mixing of the active ingredient with the other powder components. Investigations carried out for this showed that even with the dry mixing of the powder in a non-metallic mixing vessel, i. H. a glass jar, more than 5% of the active substance of the powder mixture was removed by adhesion to the container wall (glass wall).,

Example 4:

It was a powder mixture of: tricalcium phosphate 40.47 mg microcrystalline cellulose 35.00 mg Hydroxypropylcellulose, low subst. 10 mg Carboxymethyl starch sodium (Type A) 5 mg with a solution of: water 10 mg Phosphoric acid, 85% 2.38 mg disodium phosphate dihydrate 2.15 mg granulated moist.

In addition, a granulating liquid (solution, approx. 45 ° C.) was applied to the moist granulate (pregranulate): donepezil hydrochloride 5 mg ethanol 10 mg water 30 mg

applied. After drying, 19 mg of dicalcium phosphate, anhydrous and 1 mg of magnesium stearate were added to the granules. After mixing these components with the dried granules, the press-ready tabletting mixture was obtained. This was pressed into 120 mg tablets. The analytical tests of the tablets obtained gave a recovery of 99.23 +/- 0.66%.

Example 5:

It was a powder mixture of: tricalcium phosphate 39 mg Microcrystalline cellulose 38 mg Hydroxypropylcellulose, low subst. 10 mg Carboxymethyl starch sodium (Type A) 5 mg with a solution prepared at about 45 ° C: Povidone K 90 3 mg donepezil hydrochloride 5 mg water 60 mg granulated moist. After drying, 19 mg of microcrystalline cellulose, 5 mg of carboxymethyl starch sodium (type A), and 1 mg of magnesium stearate were added to the granules. After mixing these components with the dried granules, the press-ready tabletting mixture was obtained. This was pressed into 125 mg tablets.

Example 6:

It was a powder mixture of: Microcrystalline cellulose 40 mg Hydroxypropylcellulose, low subst. 5.5 mg with a solution prepared at about 45 ° C: donepezil hydrochloride 5 mg water 27 mg granulated moist. After drying, the following powder components were added to the granules: Hydroxypropylcellulose, low subst. 27.5 mg mannitol 26.1 mg Carboxymethyl starch sodium (Type A) 5 mg Glycerol 0.9 mg

After mixing these components with the dried granules, the press-ready tabletting mixture was obtained. This was pressed into tablets weighing 110 mg.

Example 7:

It was a powder mixture of: Microcrystalline cellulose 40 mg Hydroxypropylcellulose, low subst. 5.5 mg with a solution prepared at about 45 ° C: water 27 mg donepezil hydrochloride 5 mg granulated moist. After drying, 58.6 mg of mannitol and 0.9 mg of magnesium stearate were added to the granules. After mixing these components with the dried granules, the press-ready tabletting mixture was obtained. This was pressed into tablets weighing 110 mg.

Example 8:

It was a powder mixture of: Microcrystalline cellulose 40 mg Hydroxypropylcellulose, low subst. 5.5 mg with a solution prepared at about 45 ° C: water 27 mg donepezil hydrochloride 5 mg granulated moist. After drying, 58.6 mg of Emdex (glucose syrup, spray-dried) and 0.9 mg of magnesium stearate were added to the granules. After mixing these components with the dried granules, the press-ready tabletting mixture was obtained. This was compressed to 110 mg tablets of 7 mm diameter.

Example 9:

It was a powder mixture of: Microcrystalline cellulose 40 mg Hydroxypropylcellulose, low subst. 5.5 mg with a solution prepared at about 45 ° C: water 27 mg donepezil hydrochloride 5 mg granulated moist. After drying, 58.6 mg of isomalt and 0.9 mg of magnesium stearate were added to the granules. After mixing these components with the dried granules, the press-ready tabletting mixture was obtained. This was pressed into tablets weighing 110 mg.

Example 10:

It was a powder mixture of: Microcrystalline cellulose 35 mg Hydroxypropylcellulose, low subst. 5.5 mg Highly disperse silica 1.2 mg with a solution prepared at about 45 ° C: donepezil hydrochloride 5 mg water 27 mg granulated moist. After drying, 189.3 mg of BASF's Ludiflash (90% mannitol, 5% crospovidone, 5% polyvinyl acetate), 3.6 mg glycerol dibehenate and 0.4 mg magnesium stearate were added to the granules. After mixing these components with the dried granules, the press-ready tabletting mixture was obtained. This was pressed into 240 mg round orodispersible tablets 9 mm in diameter. These tablets are characterized by a particularly rapid disintegration (maximum 30 sec.) In the oral cavity to form a finely dispersed suspension.

Example 11:

It was a powder mixture of: Microcrystalline cellulose 35 mg Hydroxypropylcellulose, low subst. 5.5 mg Highly disperse silica 1.2 mg with a solution prepared at about 45 ° C: donepezil hydrochloride 5 mg water 27 mg granulated moist. After drying, 189.7 mg of BASF's Ludiflash (90% mannitol, 5% crospovidone, 5% polyvinyl acetate), 3.6 mg sodium stearyl fumarate were added to the granules. After mixing these components with the dried granules, the press-ready tabletting mixture was obtained. This was pressed into 240 mg round orodispersible tablets 9 mm in diameter. These tablets are characterized by a particularly rapid disintegration (maximum 30 sec.) In the oral cavity to form a finely dispersed suspension.

Example 12:

It was a powder mixture of: Microcrystalline cellulose 35 mg Hydroxypropylcellulose, low subst. 5.5 mg Highly disperse silica 1.2 mg with a solution prepared at about 45 ° C: donepezil hydrochloride 5 mg water 27 mg granulated moist. After drying, 66.3 mg of mannitol (Parteck M 200), 5 mg of carboxymethyl starch sodium (type A), 1.8 mg of glycerol dibehenate and 0.2 mg of magnesium stearate were added to the granules. After mixing these components with the dried granules, the press-ready tabletting mixture was obtained. This was pressed into 120 mg round 7 mm diameter tablets.

Example 13:

It was a powder mixture of: Microcrystalline cellulose 35 mg Hydroxypropylcellulose, low subst. 5.5 mg Highly disperse silica 1.2 mg with a solution prepared at about 45 ° C: donepezil hydrochloride 5 mg water 27 mg granulated moist. After drying, 67.1 mg of mannitol (Parteck M 200), 5 mg of carboxymethyl starch sodium (type A) and 1.2 mg of sodium stearyl fumarate were added to the granules. After mixing these components with the dried granules, the press-ready tabletting mixture was obtained. This was pressed into 120 mg round 7 mm diameter tablets.

Example 14:

The tablets of Example 12 were prepared by spraying an aqueous coating dispersion consisting of: hypromellose 2.3850 mg hyprolose 1.1925 mg Macrogol 6000 0.5725 mg magnesium stearate 0.14 mg Titanium dioxide 0.71 mg water 61.67 mg coated. The amount of lacquer dry matter applied per film tablet was 5 mg, so that a total film tablet weight of 125 mg was achieved.

Example 15:

The tablets of Example 13 were prepared by spraying an aqueous coating dispersion consisting of: hypromellose 2.3850 mg hyprolose 1.1925 mg Macrogol 6000 0.5725 mg magnesium stearate 0.14 mg Titanium dioxide 0.71 mg water 61.67 mg coated. The amount of lacquer dry matter applied per film tablet was 5 mg, so that a total film tablet weight of 125 mg was achieved.

Example 16:

Recovery rates of 102.01 +/- 1.08% were determined for the tablets of Example 12.

For the tablets of Example 13, recovery rates of 100.61 +/- 0.82% were determined.

Example 17:

The dissolution behavior of the film-coated tablets according to Example 14 was measured in 900 ml of 0.1N HCl while stirring at 50 revolutions per minute. The release of the drug was almost 100% within 5 min. The results are in 1 shown.

The dissolution behavior of the tablets according to Example 15 was measured in 900 ml of 0.1N HCl with stirring at 50 revolutions per minute. The release of the drug was almost 100% within 5 min. The results are in 2 shown.

Example 18:

The dissolution behavior of the tablets according to Example 14 was measured in 900 ml of acetate buffer, pH 4.6 with stirring at 50 revolutions per minute. The release of the drug was almost 100% within 5 min. The results are in 3 shown.

The dissolution behavior of the tablets according to Example 15 was measured in 900 ml of acetate buffer, pH 4.6 with stirring at 50 revolutions per minute. The release of the drug was almost 100% within 5 min. The results are in 4 shown.

Claims (11)

A process for the preparation of a tablet containing donepezil comprising the step of wet granulation of donepezil with a granulating liquid together with excipients. A method according to claim 1, characterized in that the adjuvants are selected from tablet fillers, tablet fillers, tablet binders or mixtures of these substances. A method according to claim 1 or 2, characterized in that the excipients of cellulose, microcrystalline cellulose, starch, lactose, sorbitol, mannitol, xylitol, isomalt, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, silica are selected Method according to at least one of claims 1 to 3, characterized in that the granulating liquid is selected from water, ethanol, isopropanol, n-propanol, polyethylene glycol, glycerol, acetone or mixtures of two or more of said solvents. A method according to any one of claims 1 to 4, characterized in that the weight of the tablet is 10 to 60 times the weight of the active ingredient. A method according to any one of claims 1 to 5, characterized in that the active ingredient Donepezil is used as Donepezil hydrochloride. Method according to at least one of claims 1 to 6, characterized in that a film coating takes place. Donepezil tablets obtainable by the method according to at least one of claims 1 to 7. Donepezil tablets according to claim 8, characterized in that they are uncoated tablets. Donepezil tablets according to claim 8, characterized in that they are coated tablets (film-coated tablets). Donepezil tablets according to claim 8, characterized in that they are orodispersible tablets.

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